Denosumab in patients with cancer and skeletal metastases: A systematic review and meta-analysis

Background: We conducted a systematic review of the literature to determine the efficacy and safety of denosumab in reducing skeletal-related events (SRE) in patients with bone metastases. Methods: A literature search using MEDLINE, EMBASE, Web of Science and The Cochrane Collaboration Library identified relevant controlled clinical trials up-to-March 14, 2012. Two independent reviewers assessed studies for inclusion, according to predetermined criteria, and extracted relevant data. The primary outcomes of interest were SRE, time to first on-study SRE, and overall survival. Secondary outcomes included pain, quality of life, bone turnover markers (BTM), and adverse events. Results: Six controlled trials including 6142 patients were analyzed. Compared to zoledronic acid, denosumab had lower incidence of SRE with a risk ratio (RR) of 0.84 (95% confidence intervals (CI) 0.80-0.88), delayed the onset of first on-study SRE (RR 0.83; 95% CI 0.75-0.90) and time to worsening of pain (RR 0.84; 95% CI 0.77-0.91). No difference was observed in overall survival with pooled hazard ratio of 0.98 (95% CI 0.90-1.0). For total adverse events, denosumab was similar to zoledronic acid (RR 0.97; 95% CI 0.89-1.0). No significant differences were observed in the frequency of osteonecrosis of the jaw (RR 1.4; 95% CI 0.92-2.1). Patients on denosumab had a greater risk of developing hypocalcemia (RR 1.9; 95% CI 1.6-2.3). Conclusions: Denosumab was more effective than zoledronic acid in reducing the incidence of SRE, and delayed the time to SRE. No differences were found between denosumab and zoledronic acid in reducing overall mortality, or in the frequency of overall adverse events.